CA2395461C - Procedes de modulation de la fonction kinase de proteine tyrosine de type c-kit avec des composes indolinone - Google Patents
Procedes de modulation de la fonction kinase de proteine tyrosine de type c-kit avec des composes indolinone Download PDFInfo
- Publication number
- CA2395461C CA2395461C CA2395461A CA2395461A CA2395461C CA 2395461 C CA2395461 C CA 2395461C CA 2395461 A CA2395461 A CA 2395461A CA 2395461 A CA2395461 A CA 2395461A CA 2395461 C CA2395461 C CA 2395461C
- Authority
- CA
- Canada
- Prior art keywords
- kit
- kinase
- cell
- compound
- cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 title claims abstract description 142
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 title claims abstract description 140
- 238000000034 method Methods 0.000 title claims description 71
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 title description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 154
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 53
- 230000027455 binding Effects 0.000 claims description 39
- 230000003993 interaction Effects 0.000 claims description 35
- 201000010099 disease Diseases 0.000 claims description 27
- 208000008585 mastocytosis Diseases 0.000 claims description 25
- 230000002159 abnormal effect Effects 0.000 claims description 23
- 230000019491 signal transduction Effects 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- -1 indolinone compound Chemical class 0.000 claims description 19
- 230000003197 catalytic effect Effects 0.000 claims description 16
- 206010020751 Hypersensitivity Diseases 0.000 claims description 11
- 208000026935 allergic disease Diseases 0.000 claims description 11
- 230000007815 allergy Effects 0.000 claims description 11
- 230000001404 mediated effect Effects 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 8
- 230000004075 alteration Effects 0.000 claims description 8
- 208000006673 asthma Diseases 0.000 claims description 8
- 208000005017 glioblastoma Diseases 0.000 claims description 8
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 8
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 7
- 206010003571 Astrocytoma Diseases 0.000 claims description 7
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 7
- 201000009151 chronic rhinitis Diseases 0.000 claims description 7
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 7
- 201000006512 mast cell neoplasm Diseases 0.000 claims description 7
- 206010039083 rhinitis Diseases 0.000 claims description 7
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
- 125000005248 alkyl aryloxy group Chemical group 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 238000000338 in vitro Methods 0.000 claims description 6
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 6
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 6
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 4
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Chemical group 0.000 claims description 4
- 150000002829 nitrogen Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Chemical group 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 3
- 208000010749 gastric carcinoma Diseases 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 201000000498 stomach carcinoma Diseases 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 206010057644 Testis cancer Diseases 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 201000003120 testicular cancer Diseases 0.000 claims description 2
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 1
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 50
- 206010028980 Neoplasm Diseases 0.000 abstract description 47
- 108091008598 receptor tyrosine kinases Proteins 0.000 abstract description 17
- 102000027426 receptor tyrosine kinases Human genes 0.000 abstract description 17
- 230000002062 proliferating effect Effects 0.000 abstract description 9
- 210000004027 cell Anatomy 0.000 description 114
- 108060006633 protein kinase Proteins 0.000 description 67
- 102000001253 Protein Kinase Human genes 0.000 description 66
- 210000003630 histaminocyte Anatomy 0.000 description 48
- 108090000623 proteins and genes Proteins 0.000 description 34
- 102000004169 proteins and genes Human genes 0.000 description 33
- 230000006870 function Effects 0.000 description 30
- 238000011282 treatment Methods 0.000 description 30
- 230000008859 change Effects 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- 102000005962 receptors Human genes 0.000 description 26
- 208000035475 disorder Diseases 0.000 description 25
- 108020003175 receptors Proteins 0.000 description 25
- 230000014509 gene expression Effects 0.000 description 24
- 230000005764 inhibitory process Effects 0.000 description 24
- 201000011510 cancer Diseases 0.000 description 22
- 108091000080 Phosphotransferase Proteins 0.000 description 21
- 102000020233 phosphotransferase Human genes 0.000 description 21
- 238000003556 assay Methods 0.000 description 19
- 239000003814 drug Substances 0.000 description 18
- 210000003979 eosinophil Anatomy 0.000 description 17
- 230000004663 cell proliferation Effects 0.000 description 16
- 239000000758 substrate Substances 0.000 description 14
- 238000002965 ELISA Methods 0.000 description 13
- 239000003446 ligand Substances 0.000 description 13
- 238000006366 phosphorylation reaction Methods 0.000 description 13
- 230000006907 apoptotic process Effects 0.000 description 12
- 230000003305 autocrine Effects 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 12
- 239000008280 blood Substances 0.000 description 12
- 230000026731 phosphorylation Effects 0.000 description 12
- 230000000638 stimulation Effects 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 10
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 10
- 239000006180 TBST buffer Substances 0.000 description 10
- 230000004913 activation Effects 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 230000004083 survival effect Effects 0.000 description 10
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000008194 pharmaceutical composition Substances 0.000 description 9
- 229920001184 polypeptide Polymers 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 150000001413 amino acids Chemical group 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000011161 development Methods 0.000 description 8
- 230000018109 developmental process Effects 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 230000011664 signaling Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 8
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 7
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 7
- 230000001413 cellular effect Effects 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000006184 cosolvent Substances 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 230000002209 hydrophobic effect Effects 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 229940043355 kinase inhibitor Drugs 0.000 description 7
- 230000007246 mechanism Effects 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- 230000007170 pathology Effects 0.000 description 7
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 210000000130 stem cell Anatomy 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 102100020880 Kit ligand Human genes 0.000 description 6
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 6
- 108010039445 Stem Cell Factor Proteins 0.000 description 6
- 230000033228 biological regulation Effects 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 230000024245 cell differentiation Effects 0.000 description 6
- 230000010261 cell growth Effects 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 208000032839 leukemia Diseases 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 108700020796 Oncogene Proteins 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 231100000504 carcinogenesis Toxicity 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000006166 lysate Substances 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 241000283707 Capra Species 0.000 description 4
- 208000005623 Carcinogenesis Diseases 0.000 description 4
- 102000003952 Caspase 3 Human genes 0.000 description 4
- 108090000397 Caspase 3 Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 108010002386 Interleukin-3 Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 4
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 4
- 102100037787 Protein-tyrosine kinase 2-beta Human genes 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229940100514 Syk tyrosine kinase inhibitor Drugs 0.000 description 4
- 239000013504 Triton X-100 Substances 0.000 description 4
- 229920004890 Triton X-100 Polymers 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000036952 cancer formation Effects 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 208000037976 chronic inflammation Diseases 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 210000004602 germ cell Anatomy 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 210000002510 keratinocyte Anatomy 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- 230000009870 specific binding Effects 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 210000002370 ICC Anatomy 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 206010029260 Neuroblastoma Diseases 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 108091005682 Receptor kinases Proteins 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- 201000010208 Seminoma Diseases 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 230000001640 apoptogenic effect Effects 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 230000003915 cell function Effects 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 208000023819 chronic asthma Diseases 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000035558 fertility Effects 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000000099 in vitro assay Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000010988 intraclass correlation coefficient Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 102000006240 membrane receptors Human genes 0.000 description 3
- 108020004084 membrane receptors Proteins 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 210000001550 testis Anatomy 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 102100023995 Beta-nerve growth factor Human genes 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000009458 Carcinoma in Situ Diseases 0.000 description 2
- 238000009007 Diagnostic Kit Methods 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 241000341655 Human papillomavirus type 16 Species 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 108010002616 Interleukin-5 Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 2
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 2
- 108010025020 Nerve Growth Factor Proteins 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 201000008736 Systemic mastocytosis Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001299 aldehydes Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000003782 apoptosis assay Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000001130 astrocyte Anatomy 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- OHDRQQURAXLVGJ-HLVWOLMTSA-N azane;(2e)-3-ethyl-2-[(e)-(3-ethyl-6-sulfo-1,3-benzothiazol-2-ylidene)hydrazinylidene]-1,3-benzothiazole-6-sulfonic acid Chemical compound [NH4+].[NH4+].S/1C2=CC(S([O-])(=O)=O)=CC=C2N(CC)C\1=N/N=C1/SC2=CC(S([O-])(=O)=O)=CC=C2N1CC OHDRQQURAXLVGJ-HLVWOLMTSA-N 0.000 description 2
- AFYNADDZULBEJA-UHFFFAOYSA-N bicinchoninic acid Chemical compound C1=CC=CC2=NC(C=3C=C(C4=CC=CC=C4N=3)C(=O)O)=CC(C(O)=O)=C21 AFYNADDZULBEJA-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 230000036755 cellular response Effects 0.000 description 2
- 230000004715 cellular signal transduction Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000002710 gonadal effect Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 230000011132 hemopoiesis Effects 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 201000004933 in situ carcinoma Diseases 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000004495 interstitial cells of cajal Anatomy 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 210000002332 leydig cell Anatomy 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000002752 melanocyte Anatomy 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- 230000009826 neoplastic cell growth Effects 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 150000005623 oxindoles Chemical class 0.000 description 2
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 210000004214 philadelphia chromosome Anatomy 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 210000000717 sertoli cell Anatomy 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000021595 spermatogenesis Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 125000005504 styryl group Chemical group 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- RYCSNJCJOVQGBC-UHFFFAOYSA-N 3-(1-cyclopropyl-2h-pyridin-4-yl)-1h-quinolin-2-one Chemical class O=C1NC2=CC=CC=C2C=C1C(C=C1)=CCN1C1CC1 RYCSNJCJOVQGBC-UHFFFAOYSA-N 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 201000008217 Aggressive systemic mastocytosis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 101100215673 Arabidopsis thaliana AGL11 gene Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- OGBVRMYSNSKIEF-UHFFFAOYSA-N Benzylphosphonic acid Chemical class OP(O)(=O)CC1=CC=CC=C1 OGBVRMYSNSKIEF-UHFFFAOYSA-N 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000005701 Calcium-Binding Proteins Human genes 0.000 description 1
- 108010045403 Calcium-Binding Proteins Proteins 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000006343 Cutaneous Mastocytosis Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010054814 DNA Gyrase Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100023688 Eotaxin Human genes 0.000 description 1
- 101710139422 Eotaxin Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
- 108091006109 GTPases Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102000016285 Guanine Nucleotide Exchange Factors Human genes 0.000 description 1
- 108010067218 Guanine Nucleotide Exchange Factors Proteins 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001059535 Homo sapiens Megakaryocyte-associated tyrosine-protein kinase Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 102100039064 Interleukin-3 Human genes 0.000 description 1
- 102000000743 Interleukin-5 Human genes 0.000 description 1
- 201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000035268 Mast Cell Activation disease Diseases 0.000 description 1
- 102100028905 Megakaryocyte-associated tyrosine-protein kinase Human genes 0.000 description 1
- 208000007727 Muscle Tissue Neoplasms Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 208000009905 Neurofibromatoses Diseases 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 241000609499 Palicourea Species 0.000 description 1
- 101000909992 Papio hamadryas Chymase Proteins 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000009658 Peptidylprolyl Isomerase Human genes 0.000 description 1
- 108010020062 Peptidylprolyl Isomerase Proteins 0.000 description 1
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 102000015439 Phospholipases Human genes 0.000 description 1
- 108010064785 Phospholipases Proteins 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 1
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920002642 Polysorbate 65 Polymers 0.000 description 1
- 101710093543 Probable non-specific lipid-transfer protein Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 229940123924 Protein kinase C inhibitor Drugs 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 108700025701 Retinoblastoma Genes Proteins 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 102000000395 SH3 domains Human genes 0.000 description 1
- 108050008861 SH3 domains Proteins 0.000 description 1
- 101150073911 STK gene Proteins 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 206010046752 Urticaria Pigmentosa Diseases 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 101000752225 Xenopus laevis Low density lipoprotein receptor adapter protein 1-A Proteins 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000021592 benign granular cell tumor Diseases 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004271 bone marrow stromal cell Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 102000036109 cAMP binding proteins Human genes 0.000 description 1
- 108091010966 cAMP binding proteins Proteins 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 108020001778 catalytic domains Proteins 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000006727 cell loss Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000010001 cellular homeostasis Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000005482 chemotactic factor Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000009668 clonal growth Effects 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 210000001608 connective tissue cell Anatomy 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 210000005002 female reproductive tract Anatomy 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 230000003352 fibrogenic effect Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 108091005608 glycosylated proteins Proteins 0.000 description 1
- 102000035122 glycosylated proteins Human genes 0.000 description 1
- 210000002503 granulosa cell Anatomy 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 210000004024 hepatic stellate cell Anatomy 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 210000005024 intraepithelial lymphocyte Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 208000030179 maculopapular cutaneous mastocytosis Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000003794 male germ cell Anatomy 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000032123 mast cell apoptotic process Effects 0.000 description 1
- 208000000516 mast-cell leukemia Diseases 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 201000008806 mesenchymal cell neoplasm Diseases 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 201000004130 myoblastoma Diseases 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 230000006654 negative regulation of apoptotic process Effects 0.000 description 1
- 230000007302 negative regulation of cytokine production Effects 0.000 description 1
- 230000031987 negative regulation of mast cell apoptotic process Effects 0.000 description 1
- 230000027405 negative regulation of phosphorylation Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000010309 neoplastic transformation Effects 0.000 description 1
- 201000004931 neurofibromatosis Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000034004 oogenesis Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000009696 proliferative response Effects 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000003881 protein kinase C inhibitor Substances 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 230000029983 protein stabilization Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 125000004076 pyridyl group Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 230000022932 ruffle assembly Effects 0.000 description 1
- 210000004116 schwann cell Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 150000003346 selenoethers Chemical class 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 108010002164 tyrosine receptor Proteins 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Child & Adolescent Psychology (AREA)
- Obesity (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Reproductive Health (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
L'invention concerne des composés et leur utilisation pour inhiber l'activité d'une kinase tyrosine réceptrice. L'invention s'utilise de préférence pour traiter des troubles dus à la prolifération cellulaire tels que des cancers, caractérisés par une suractivité ou une activité inappropriée de la kinase de type c-kit.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US17169399P | 1999-12-22 | 1999-12-22 | |
| US60/171,693 | 1999-12-22 | ||
| PCT/US2000/035009 WO2001045689A2 (fr) | 1999-12-22 | 2000-12-22 | PROCEDES DE MODULATION DE LA FONCTION KINASE DE PROTEINE TYROSINE DE TYPE c-KIT AVEC DES COMPOSES INDOLINONE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2395461A1 CA2395461A1 (fr) | 2001-06-28 |
| CA2395461C true CA2395461C (fr) | 2010-05-25 |
Family
ID=22624773
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2395461A Expired - Lifetime CA2395461C (fr) | 1999-12-22 | 2000-12-22 | Procedes de modulation de la fonction kinase de proteine tyrosine de type c-kit avec des composes indolinone |
Country Status (14)
| Country | Link |
|---|---|
| US (3) | US20020010203A1 (fr) |
| EP (1) | EP1255536B1 (fr) |
| JP (1) | JP5004392B2 (fr) |
| AT (1) | ATE331514T1 (fr) |
| AU (1) | AU784266B2 (fr) |
| CA (1) | CA2395461C (fr) |
| CY (1) | CY1106165T1 (fr) |
| DE (1) | DE60029138T2 (fr) |
| DK (1) | DK1255536T3 (fr) |
| ES (1) | ES2267605T3 (fr) |
| MX (1) | MXPA02006263A (fr) |
| NZ (1) | NZ519697A (fr) |
| PT (1) | PT1255536E (fr) |
| WO (1) | WO2001045689A2 (fr) |
Families Citing this family (117)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8048629B2 (en) * | 1996-03-15 | 2011-11-01 | The Penn State Research Foundation | Detection of extracellular tumor-associated nucleic acid in blood plasma or serum |
| EP0929694A4 (fr) | 1996-03-15 | 2002-05-02 | Penn State Res Found | Detection d'acide nucleique extracellulaire lie a des tumeurs dans le plasma ou le serum sanguin a l'aide d'essais d'amplification d'acide nucleique |
| HRP20020751B1 (hr) * | 2000-02-15 | 2011-01-31 | Sugen | Pirolom supstituirani 2-indolinoni kao inhibitori protein kinaze |
| KR100600550B1 (ko) * | 2000-10-20 | 2006-07-13 | 에자이 가부시키가이샤 | 질소 함유 방향환 유도체 |
| ATE330608T1 (de) | 2001-06-29 | 2006-07-15 | Ab Science | Die verwendung von n-phenyl-2-pyrimidine-amine derivaten zur behandlung von entzündlichen erkrankungen |
| WO2003003006A2 (fr) | 2001-06-29 | 2003-01-09 | Ab Science | Nouveaux inhibiteurs selectifs puissants et non toxiques de c-kit |
| WO2003002107A2 (fr) * | 2001-06-29 | 2003-01-09 | Ab Science | Utilisation d'inhibiteurs de tyrosine kinase dans le traitement de la sclerose en plaques |
| JP2005503361A (ja) * | 2001-06-29 | 2005-02-03 | アブ サイエンス | 肥満細胞症治療のための強力で選択的かつ非毒性のｃ−ｋｉｔ阻害剤の使用 |
| ES2274993T3 (es) * | 2001-06-29 | 2007-06-01 | Ab Science | Utilizacion de inhibidores de tirosina cinasa para el tratamiento de enfermedades alergicas. |
| DE60227709D1 (de) * | 2001-06-29 | 2008-08-28 | Ab Science | Die verwendung von c-kithemmern zur behandlung von autoimmunerkrankungen |
| JP2004530730A (ja) * | 2001-06-29 | 2004-10-07 | アブ サイエンス | 腫瘍の血管新生を治療するための強力で選択的かつ非毒性のｃ−ｋｉｔ阻害剤の使用法 |
| WO2003002105A2 (fr) * | 2001-06-29 | 2003-01-09 | Ab Science | Utilisation d'inhibiteurs de la tyrosine kinase dans le traitement de la perte osseuse |
| PT1401416E (pt) | 2001-06-29 | 2007-02-28 | Ab Science | Utilização de inibidores de c-kit para tratar doenças inflamatórias intestinais (dii) |
| AR038957A1 (es) * | 2001-08-15 | 2005-02-02 | Pharmacia Corp | Terapia de combinacion para el tratamiento del cancer |
| EP2277991A1 (fr) * | 2001-08-21 | 2011-01-26 | Ventana Medical Systems, Inc. | Procédé et essai de quantification permettant d'évaluer du système c-kit/scf/pakt |
| DE60225590T2 (de) * | 2001-09-20 | 2008-09-25 | Ab Science | C-kithemmer zur behandlung von bakteriellen infektionen |
| CA2460845A1 (fr) * | 2001-09-20 | 2003-03-27 | Ab Science | Utilisation d'inhibiteurs c-kit puissants, selectifs et non toxiques pour le traitement de la cystopathie interstitielle sous-muqueuse |
| EP1461032B1 (fr) * | 2001-09-20 | 2008-07-16 | AB Science | Utilisation d'inhibiteurs de la c-kit pour stimuler la pousse des cheveux |
| TWI259081B (en) * | 2001-10-26 | 2006-08-01 | Sugen Inc | Treatment of acute myeloid leukemia with indolinone compounds |
| EP1439834A1 (fr) * | 2001-10-30 | 2004-07-28 | Applied Research Systems ARS Holding N.V. | Oxindoles hydrazides modulateurs des proteines tyrosines phosphatases (ptps) |
| JP2005528344A (ja) | 2002-02-15 | 2005-09-22 | ファルマシア・アンド・アップジョン・カンパニー・エルエルシー | インドリノン誘導体の製造法 |
| PT1478380E (pt) * | 2002-02-27 | 2006-12-29 | Ab Science | Utilização de inibidores de tirosina-cinases para tratar doenças do snc |
| EP1347041A1 (fr) * | 2002-03-21 | 2003-09-24 | Universitätsklinikum Benjamin Franklin der Freien Universität Berlin | Lignée cellulaire de mammifères independantes des facteurs de croissance et une méthode pour sa préparation |
| US20050032871A1 (en) * | 2002-09-03 | 2005-02-10 | Sugen, Inc. | Sulfonylated pyrrole-2-indolinone derivatives as kinase inhibitors |
| FR2844452A1 (fr) * | 2002-09-18 | 2004-03-19 | Inst Gustave Roussy Igr | Utilisation d'inhibiteurs specifiques de tyrosine kinases pour l'immunomodulation |
| AR042042A1 (es) * | 2002-11-15 | 2005-06-08 | Sugen Inc | Administracion combinada de una indolinona con un agente quimioterapeutico para trastornos de proliferacion celular |
| US7452913B2 (en) * | 2003-02-24 | 2008-11-18 | Pharmacia & Upjohn Company | Polymorphs of pyrrole substituted 2-indolinone protein kinase inhibitors |
| EP1604665B1 (fr) * | 2003-03-10 | 2011-05-11 | Eisai R&D Management Co., Ltd. | Inhibiteur de kinase c-kit |
| JP4303726B2 (ja) | 2003-11-11 | 2009-07-29 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ウレア誘導体およびその製造方法 |
| JP5138938B2 (ja) | 2003-12-19 | 2013-02-06 | プレキシコン インコーポレーテッド | Ｒｅｔ調節剤の開発のための化合物および方法 |
| WO2006001954A2 (fr) * | 2004-05-20 | 2006-01-05 | Puget Sound Blood Center And Program | Procedes favorisant la formation de plaquettes et permettant le traitement de troubles du sang et de la moelle osseuse |
| US7498342B2 (en) * | 2004-06-17 | 2009-03-03 | Plexxikon, Inc. | Compounds modulating c-kit activity |
| TW200616632A (en) * | 2004-06-17 | 2006-06-01 | Plexxikon Inc | Compounds modulating c-kit activity and uses therefor |
| US8969379B2 (en) | 2004-09-17 | 2015-03-03 | Eisai R&D Management Co., Ltd. | Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7=methoxy-6-quinolinecarboxide |
| AU2006272951A1 (en) * | 2005-05-17 | 2007-02-01 | Plexxikon, Inc. | Pyrrol (2,3-b) pyridine derivatives protein kinase inhibitors |
| MY153898A (en) * | 2005-06-22 | 2015-04-15 | Plexxikon Inc | Compounds and methods for kinase modulation, and indications therefor |
| JP5066446B2 (ja) * | 2005-08-01 | 2012-11-07 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管新生阻害物質の効果を予測する方法 |
| JP4989476B2 (ja) | 2005-08-02 | 2012-08-01 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管新生阻害物質の効果を検定する方法 |
| US7754717B2 (en) | 2005-08-15 | 2010-07-13 | Amgen Inc. | Bis-aryl amide compounds and methods of use |
| CN102716490A (zh) * | 2005-09-01 | 2012-10-10 | 卫材R&D管理有限公司 | 药物组合物的崩解性的改善方法 |
| RU2399619C2 (ru) | 2005-09-19 | 2010-09-20 | Пфайзер Продактс Инк. | Твердые солевые формы замещенного пирролом 2-индолинона |
| US20080274469A1 (en) | 2005-10-21 | 2008-11-06 | The Regents Of The University Of California | C-Kit Oncogene Mutations in Melanoma |
| KR101353763B1 (ko) | 2005-11-07 | 2014-01-21 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 혈관 신생 저해 물질과 ｃ―ｋｉｔ 키나아제 저해 물질의병용 |
| US20090247576A1 (en) * | 2005-11-22 | 2009-10-01 | Eisai R & D Management Co., Ltd. | Anti-tumor agent for multiple myeloma |
| CN104706637A (zh) * | 2006-05-18 | 2015-06-17 | 卫材R&D管理有限公司 | 针对甲状腺癌的抗肿瘤剂 |
| US20090203693A1 (en) * | 2006-06-29 | 2009-08-13 | Eisai R & D Management Co., Ltd. | Therapeutic agent for liver fibrosis |
| EP2079724B1 (fr) | 2006-07-20 | 2010-05-26 | Amgen Inc. | Composés de pyridone substitués et procédés d'utilisation |
| CA2658190C (fr) | 2006-07-20 | 2013-01-29 | Amgen Inc. | Composes heterocycliques a bi-substitution amino et procedes d'utilisation |
| US8048411B2 (en) * | 2006-08-17 | 2011-11-01 | The Cleveland Clinic Foundation | Co-transplantation of hepatic stellate cells and islet cells |
| JP5368096B2 (ja) * | 2006-08-28 | 2013-12-18 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 未分化型胃癌に対する抗腫瘍剤 |
| AU2007296740B2 (en) * | 2006-09-11 | 2012-09-27 | Curis, Inc. | Substituted 2-indolinone as PTK inhibitors containing a zinc binding moiety |
| WO2008063888A2 (fr) | 2006-11-22 | 2008-05-29 | Plexxikon, Inc. | Composés modulant l'activité de c-fms et/ou de c-kit et utilisations associées |
| WO2008079909A1 (fr) * | 2006-12-21 | 2008-07-03 | Plexxikon, Inc. | Composés et méthodes de modulation des kinases, et indications connexes |
| PE20121126A1 (es) * | 2006-12-21 | 2012-08-24 | Plexxikon Inc | Compuestos pirrolo [2,3-b] piridinas como moduladores de quinasa |
| RU2009122670A (ru) | 2006-12-21 | 2011-01-27 | Плекссикон, Инк. (Us) | Соединения и способы для модуляции киназ и показания к их применению |
| WO2008093855A1 (fr) | 2007-01-29 | 2008-08-07 | Eisai R & D Management Co., Ltd. | Composition destinée au traitement d'un cancer de l'estomac de type indifférencié |
| WO2008138184A1 (fr) * | 2007-05-14 | 2008-11-20 | Shanghai Hengrui Pharmaceutical Co.Ltd. | Dérivés de pyrrolo-azacycles, leur procédé de fabrication et leur utilisation en tant qu'inhibiteurs de protéine kinases |
| JP2010533729A (ja) | 2007-07-17 | 2010-10-28 | プレキシコン，インコーポレーテッド | キナーゼ調節のための化合物と方法、及びそのための適応 |
| CA2704000C (fr) | 2007-11-09 | 2016-12-13 | Eisai R&D Management Co., Ltd. | Combinaison d'une substance antiangiogenique et d'un complexe de platine antitumoral |
| EP2068152A1 (fr) | 2007-12-06 | 2009-06-10 | Max-Delbrück-Centrum für Molekulare Medizin (MDC) | c-Kit en tant que nouvelle cible pour le traitement de la douleur |
| WO2009096377A1 (fr) * | 2008-01-29 | 2009-08-06 | Eisai R & D Management Co., Ltd. | Utilisation combinée d'un inhibiteur de l'angiogenèse et d'un taxane |
| EP2090306A1 (fr) | 2008-02-13 | 2009-08-19 | Ratiopharm GmbH | Compositions pharmaceutiques comportant du N-[2-(diethylamino)ethyl]-5-[5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide |
| EP2113248A1 (fr) | 2008-04-29 | 2009-11-04 | Ratiopharm GmbH | Composition pharmaceutique comportant du N-[2-(diethylamino)ethyl]-5-[5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2-dimethyl-1H-pyrrole-3-carboxamide |
| EP2098521A1 (fr) | 2008-03-06 | 2009-09-09 | Ratiopharm GmbH | Formules cristallines de N-[2-(diéthylamino)éthyl]-5-[5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidène)méthyl]-2,4-diméthyl-1H-pyrrole-3-carboxamide |
| EP2138167A1 (fr) | 2008-06-24 | 2009-12-30 | ratiopharm GmbH | Compositions pharmaceutiques comportant du N-[2-(diethylamino)ethyl]-5-[5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide |
| WO2010017541A2 (fr) | 2008-08-08 | 2010-02-11 | The Johns Hopkins University | Compositions et procédés de traitement d'une maladie dégénérative du système nerveux |
| WO2010098888A1 (fr) * | 2009-02-27 | 2010-09-02 | Massachusetts Institute Of Technology | Utilisations de produits chimiques pour moduler la signalisation par gsk–3 pour le traitement d'un trouble bipolaire et autres troubles cérébraux |
| CA2738573C (fr) * | 2009-04-03 | 2013-02-19 | F. Hoffmann-La Roche Ag | Compositions et utilisations associees |
| CN101885698B (zh) * | 2009-05-15 | 2012-07-11 | 浙江海正药业股份有限公司 | 一种吡咯基丙烯酰胺类化合物及其在舒尼替尼合成中的应用 |
| EP2255792A1 (fr) | 2009-05-20 | 2010-12-01 | Ratiopharm GmbH | Composition pharmaceutique pour n-[2-(diethylamino)ethyl]5-[(fluoro-1,2-dihydro-2-oxo-3H-indole-3-ylidene) methyl]-2,4-dimenthyl-1h-pyrrole-3-carboxamide |
| EP2264027A1 (fr) | 2009-05-27 | 2010-12-22 | Ratiopharm GmbH | Processus pour la préparation de N-[2-(diethylamino)ethyl]-5-[5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide |
| US8329724B2 (en) | 2009-08-03 | 2012-12-11 | Hoffmann-La Roche Inc. | Process for the manufacture of pharmaceutically active compounds |
| CA2771403C (fr) | 2009-08-19 | 2015-02-24 | Eisai R&D Management Co. Ltd. | Composition pharmaceutique contenant un derive de quinoleine |
| JP2013510166A (ja) | 2009-11-06 | 2013-03-21 | プレキシコン インコーポレーテッド | キナーゼ調節のための化合物、方法およびその適用 |
| CN102724967A (zh) * | 2009-12-31 | 2012-10-10 | 安龙制药公司 | 包括可释放的脲连接体的含芳香胺化合物的聚合缀合物 |
| US10166142B2 (en) | 2010-01-29 | 2019-01-01 | Forsight Vision4, Inc. | Small molecule delivery with implantable therapeutic device |
| WO2011119777A2 (fr) | 2010-03-23 | 2011-09-29 | The Johns Hopkins University | Compositions et méthodes de traitement d'une maladie neurodégénérative |
| CN102958523B (zh) | 2010-06-25 | 2014-11-19 | 卫材R&D管理有限公司 | 使用具有激酶抑制作用的组合的抗肿瘤剂 |
| US20120076797A1 (en) * | 2010-07-14 | 2012-03-29 | Butte Atul J | Modulation of kit signaling and hematopoietic cell development by IL-4 receptor modulation |
| WO2012027716A1 (fr) | 2010-08-27 | 2012-03-01 | Collabrx, Inc. | Procédé pour traiter un mélanome chez des sujets résistants à un inhibiteur de braf |
| WO2012042421A1 (fr) | 2010-09-29 | 2012-04-05 | Pfizer Inc. | Procédé de traitement de la croissance cellulaire anormale |
| WO2012068487A1 (fr) | 2010-11-18 | 2012-05-24 | Synta Pharmaceuticals Corp. | Présélection de patients pour un traitement thérapeutique fondé sur un état hypoxique, avec des agents sensibles à l'oxygène |
| WO2012068549A2 (fr) | 2010-11-19 | 2012-05-24 | Forsight Vision4, Inc. | Formulations d'agents thérapeutiques pour des dispositifs implantés |
| US10220020B2 (en) | 2010-12-23 | 2019-03-05 | Nektar Therapeutics | Polymer-des-ethyl sunitinib conjugates |
| US9827326B2 (en) | 2010-12-23 | 2017-11-28 | Nektar Therapeutics | Polymer-sunitinib conjugates |
| US20120189633A1 (en) | 2011-01-26 | 2012-07-26 | Kolltan Pharmaceuticals, Inc. | Anti-kit antibodies and uses thereof |
| PE20141360A1 (es) | 2011-02-07 | 2014-10-13 | Plexxikon Inc | Compuestos y metodos para la modulacion de quinasas e indicaciones para los mismos. |
| TWI558702B (zh) | 2011-02-21 | 2016-11-21 | 普雷辛肯公司 | 醫藥活性物質的固態形式 |
| US8630703B2 (en) | 2011-03-09 | 2014-01-14 | Technion Research & Development Foundation Limited | Treatment utilizing hydrophobic weak bases chemotherapeutic agents and illumination |
| AU2012246490B2 (en) | 2011-04-18 | 2016-08-04 | Eisai R&D Management Co., Ltd. | Therapeutic agent for tumor |
| JP6038128B2 (ja) | 2011-06-03 | 2016-12-07 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | レンバチニブ化合物に対する甲状腺癌対象及び腎臓癌対象の反応性を予測及び評価するためのバイオマーカー |
| US9150570B2 (en) | 2012-05-31 | 2015-10-06 | Plexxikon Inc. | Synthesis of heterocyclic compounds |
| EP4063391A1 (fr) | 2012-07-25 | 2022-09-28 | Celldex Therapeutics, Inc. | Anticorps anti-kit et leurs utilisations |
| JP6318156B2 (ja) | 2012-09-06 | 2018-04-25 | プレキシコン インコーポレーテッドＰｌｅｘｘｉｋｏｎ Ｉｎｃ． | キナーゼをモジュレートするための化合物および方法、ならびにその指標 |
| EP2895170A4 (fr) * | 2012-09-14 | 2016-07-20 | Childrens Medical Center | Inhibition de l'asthme déclenché par une infection virale par un inhibiteur de c-kit |
| ME03000B (fr) | 2012-12-21 | 2018-10-20 | Plexxikon Inc | Composés et procédés pour la modulation de kinase, et indications associées |
| JPWO2014098176A1 (ja) | 2012-12-21 | 2017-01-12 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | キノリン誘導体のアモルファス及びその製造方法 |
| EP2968113B8 (fr) | 2013-03-14 | 2020-10-28 | Forsight Vision4, Inc. | Systèmes pour l'administration intra-oculaire entretenue de composés à faible solubilité provenant d'un implant de système de pose d'orifice |
| CA2912219C (fr) | 2013-05-14 | 2021-11-16 | Eisai R&D Management Co., Ltd. | Biomarqueurs pour predire et evaluer la reponse de sujets atteints de cancer de l'endometre a des composes a base de lenvatinib |
| US10450295B2 (en) * | 2013-08-09 | 2019-10-22 | Acclaim BioMed USA LLC | Method of using an indolinone molecule and derivatives for inhibiting liver fibrosis and hepatitis |
| US11136625B2 (en) | 2013-08-28 | 2021-10-05 | Crown Bioscience, Inc. (Taicang) | Gene expression signatures predictive of subject response to a multi-kinase inhibitor and methods of using the same |
| US9771369B2 (en) | 2014-03-04 | 2017-09-26 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| JP6768639B2 (ja) * | 2014-05-23 | 2020-10-21 | セルデックス セラピューティクス，インコーポレーテッド | 好酸球又はマスト細胞関連障害の治療 |
| KR20170040798A (ko) | 2014-08-08 | 2017-04-13 | 포사이트 비젼4, 인크. | 수용체 티로신 키나제 억제제의 안정한 가용성 제제 및 그의 제조 방법 |
| EP3187491A4 (fr) | 2014-08-28 | 2018-08-01 | Eisai R&D Management Co., Ltd. | Dérivé de quinoline de pureté élevée et son procédé de fabrication |
| US20180028662A1 (en) | 2015-02-25 | 2018-02-01 | Eisai R&D Management Co., Ltd. | Method for Suppressing Bitterness of Quinoline Derivative |
| KR20240064733A (ko) | 2015-03-04 | 2024-05-13 | 머크 샤프 앤드 돔 코포레이션 | 암을 치료하기 위한 pd-1 길항제 및 vegfr/fgfr/ret 티로신 키나제 억제제의 조합 |
| WO2016184793A1 (fr) | 2015-05-15 | 2016-11-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Méthodes de traitement de patients souffrant d'un adénocarcinome rénal métastatique résistant aux inhibiteurs du vegfr |
| CA2988707C (fr) | 2015-06-16 | 2023-10-10 | Eisai R&D Management Co., Ltd. | Combinaison de proteine se liant au cre/inhibiteur de catenine et d'un inhibiteur de point de controle immunitaire servant au traitement du cancer |
| CN108135894B (zh) | 2015-08-20 | 2021-02-19 | 卫材R&D管理有限公司 | 肿瘤治疗剂 |
| KR20180058758A (ko) | 2015-09-22 | 2018-06-01 | 그레이버그 비젼, 인크. | 안구 장애의 치료를 위한 화합물 및 조성물 |
| CN110072528B (zh) | 2017-02-08 | 2022-04-26 | 卫材R&D管理有限公司 | 治疗肿瘤的药物组合物 |
| MX2019011242A (es) | 2017-03-23 | 2020-01-21 | Graybug Vision Inc | Farmacos y composiciones para el tratamiento de trastornos oculares. |
| MX2019013363A (es) | 2017-05-10 | 2020-01-13 | Graybug Vision Inc | Microparticulas de liberacion extendida y suspensiones de las mismas para terapia medica. |
| WO2018212202A1 (fr) | 2017-05-16 | 2018-11-22 | Eisai R&D Management Co., Ltd. | Traitement du carcinome hépatocellulaire |
| AU2021263383A1 (en) | 2020-04-29 | 2022-11-24 | Plexxikon Inc. | Synthesis of heterocyclic compounds |
| US20250129067A1 (en) | 2021-11-08 | 2025-04-24 | Progentos Therapeutics, Inc. | Platelet-derived growth factor receptor (pdgfr) alpha inhibitors and uses thereof |
Family Cites Families (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4376110A (en) | 1980-08-04 | 1983-03-08 | Hybritech, Incorporated | Immunometric assays using monoclonal antibodies |
| US4966849A (en) | 1985-09-20 | 1990-10-30 | President And Fellows Of Harvard College | CDNA and genes for human angiogenin (angiogenesis factor) and methods of expression |
| US5217999A (en) | 1987-12-24 | 1993-06-08 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Styryl compounds which inhibit EGF receptor protein tyrosine kinase |
| ES2064101T3 (es) | 1990-04-02 | 1995-01-16 | Pfizer | Compuestos de acido bencilfosfonico inhibidores de la quinasa de tirosina. |
| DE69222637T2 (de) | 1991-05-10 | 1998-02-26 | Rhone Poulenc Rorer Int | Bis mono- und bicyclische aryl- und heteroarylderivate mit inhibierender wirkung auf die egf und/oder pdgf-rezeptor tyrosinkinase |
| JPH06503095A (ja) | 1991-05-29 | 1994-04-07 | ファイザー・インコーポレーテッド | 三環式ポリヒドロキシ系のチロシンキナーゼ阻害薬 |
| EP0654024A1 (fr) | 1992-08-06 | 1995-05-24 | Warner-Lambert Company | 2-thioindoles (selenoindoles) et disulfures associes (seleniures) inhibant les tyrosine kinases et presentant des proprietes antitumorales |
| US5330992A (en) | 1992-10-23 | 1994-07-19 | Sterling Winthrop Inc. | 1-cyclopropyl-4-pyridyl-quinolinones |
| KR100335584B1 (ko) | 1992-10-28 | 2002-11-29 | 제넨테크, 인코포레이티드 | 혈관내피세포성장인자에대한길항제 |
| GB9226855D0 (en) | 1992-12-23 | 1993-02-17 | Erba Carlo Spa | Vinylene-azaindole derivatives and process for their preparation |
| GB9501567D0 (en) | 1995-01-26 | 1995-03-15 | Pharmacia Spa | Hydrosoluble 3-arylidene-2-oxindole derivatives as tyrosine kinase inhibitors |
| US5880141A (en) * | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
| GB9611797D0 (en) * | 1996-06-06 | 1996-08-07 | Pharmacia Spa | Substituted quinolylmethylen-oxindole analogues as tyrosine kinase inhibitors |
| EP0929520B1 (fr) * | 1996-08-23 | 2005-11-02 | Sugen, Inc. | Banques combinatoires d'indolinone, produits et procedes associes pour traiter des maladies |
| AU6887698A (en) * | 1997-04-08 | 1998-10-30 | Sugen, Inc. | Study and treatment of diseases related to specific cellular functions of receptor protein tyrosine kinases |
| CA2289102A1 (fr) * | 1997-05-07 | 1998-11-12 | Sugen, Inc. | Derives de 2-indolinone utilises en tant que modulateurs de l'activite de la proteine kinase |
| ES2205531T3 (es) | 1997-08-02 | 2004-05-01 | THE PROCTER & GAMBLE COMPANY | Procedimiento para prparar tensioactivos de alcoholes poli(oxialquilados)rematados con eteres. |
| GB9716557D0 (en) | 1997-08-06 | 1997-10-08 | Glaxo Group Ltd | Benzylidene-1,3-dihydro-indol-2-one derivatives having anti-cancer activity |
| WO1999048868A2 (fr) * | 1998-03-26 | 1999-09-30 | Sugen, Inc. | Familles heterocycliques de composes destinees a la modulation de la tyrosine-kinase |
| US6514981B1 (en) | 1998-04-02 | 2003-02-04 | Sugen, Inc. | Methods of modulating tyrosine protein kinase function with indolinone compounds |
| KR100743287B1 (ko) * | 1998-05-29 | 2007-07-26 | 수젠, 인크. | 피롤기로 치환된 2-인돌리논 단백질 인산화 효소 억제제 |
| DE69906152T2 (de) * | 1998-12-17 | 2004-02-12 | F. Hoffmann-La Roche Ag | 4-alkenyl (und alkinyl)oxoindole als inhibitoren cyclinabhängiger kinasen, insbesondere cdk2 |
| US6689806B1 (en) * | 1999-03-24 | 2004-02-10 | Sugen, Inc. | Indolinone compounds as kinase inhibitors |
| AU3770000A (en) * | 1999-03-24 | 2000-10-09 | Sugen, Inc. | Indolinone compounds as kinase inhibitors |
| JP5336686B2 (ja) * | 1999-11-24 | 2013-11-06 | スージェン， インク． | 遊離酸または遊離塩基としてイオン化可能な医薬品のための処方 |
| US6878733B1 (en) * | 1999-11-24 | 2005-04-12 | Sugen, Inc. | Formulations for pharmaceutical agents ionizable as free acids or free bases |
| US6339100B1 (en) * | 1999-12-29 | 2002-01-15 | The Trustees Of Columbia University In The City Of New York | Methods for inhibiting mastocytosis |
-
2000
- 2000-12-22 CA CA2395461A patent/CA2395461C/fr not_active Expired - Lifetime
- 2000-12-22 MX MXPA02006263A patent/MXPA02006263A/es active IP Right Grant
- 2000-12-22 NZ NZ519697A patent/NZ519697A/en unknown
- 2000-12-22 AT AT00991704T patent/ATE331514T1/de not_active IP Right Cessation
- 2000-12-22 EP EP00991704A patent/EP1255536B1/fr not_active Expired - Lifetime
- 2000-12-22 ES ES00991704T patent/ES2267605T3/es not_active Expired - Lifetime
- 2000-12-22 DE DE60029138T patent/DE60029138T2/de not_active Expired - Lifetime
- 2000-12-22 PT PT00991704T patent/PT1255536E/pt unknown
- 2000-12-22 AU AU34363/01A patent/AU784266B2/en not_active Ceased
- 2000-12-22 US US09/741,842 patent/US20020010203A1/en not_active Abandoned
- 2000-12-22 DK DK00991704T patent/DK1255536T3/da active
- 2000-12-22 JP JP2001546428A patent/JP5004392B2/ja not_active Expired - Lifetime
- 2000-12-22 WO PCT/US2000/035009 patent/WO2001045689A2/fr not_active Ceased
-
2003
- 2003-06-23 US US10/600,868 patent/US20040002534A1/en not_active Abandoned
-
2005
- 2005-08-16 US US11/205,474 patent/US7211600B2/en not_active Expired - Lifetime
-
2006
- 2006-09-20 CY CY20061101345T patent/CY1106165T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA02006263A (es) | 2004-02-26 |
| HK1050642A1 (en) | 2003-07-04 |
| CA2395461A1 (fr) | 2001-06-28 |
| US20040002534A1 (en) | 2004-01-01 |
| WO2001045689A2 (fr) | 2001-06-28 |
| DE60029138D1 (de) | 2006-08-10 |
| ES2267605T3 (es) | 2007-03-16 |
| DK1255536T3 (da) | 2006-10-30 |
| ATE331514T1 (de) | 2006-07-15 |
| AU3436301A (en) | 2001-07-03 |
| EP1255536A2 (fr) | 2002-11-13 |
| PT1255536E (pt) | 2006-09-29 |
| EP1255536B1 (fr) | 2006-06-28 |
| AU784266B2 (en) | 2006-03-02 |
| JP5004392B2 (ja) | 2012-08-22 |
| US7211600B2 (en) | 2007-05-01 |
| US20050288353A1 (en) | 2005-12-29 |
| US20020010203A1 (en) | 2002-01-24 |
| NZ519697A (en) | 2004-08-27 |
| JP2004500363A (ja) | 2004-01-08 |
| CY1106165T1 (el) | 2011-06-08 |
| WO2001045689A3 (fr) | 2002-01-03 |
| DE60029138T2 (de) | 2007-06-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU784266B2 (en) | Indolinone derivatives for modulation of c-kit tyrosine kinase | |
| US6239161B1 (en) | Method and compositions for inhibition of adaptor protein/tyrosine kinase interactions | |
| Lennartsson et al. | Normal and oncogenic forms of the receptor tyrosine kinase kit | |
| US6235769B1 (en) | Methods of preventing and treating neurological disorders with compounds that modulate the function of the C-RET receptor protein tyrosine kinase | |
| US20060058339A1 (en) | Compounds modulating c-kit activity and uses therefor | |
| US6660763B2 (en) | Bis-indolylquinone compounds | |
| CA2368041A1 (fr) | Composes d'indolinone tels que des inhibiteurs de kinase | |
| WO2012125904A1 (fr) | Composés imitant des mutations qui se lient au domaine kinase de l'egfr | |
| Dobrusin et al. | Protein tyrosine kinases and cancer | |
| Pflug et al. | Cyanine dye conjugation enhances crizotinib localization to intracranial tumors, attenuating NF-κB-inducing kinase activity and glioma progression | |
| CN100389829C (zh) | 用于抑制肿瘤性损伤的化合物的鉴定方法和含所述化合物的药物组合物 | |
| HK1050642B (en) | Indolinone derivatives for modulation of c-kit tyrosine protein kinase | |
| WO2004024145A1 (fr) | Action anticancereuse du carvedilol et de ses isomeres | |
| US20150065486A1 (en) | Methods for treating polycystic kidney disease | |
| AU780046B2 (en) | A method for screening compounds for their potential to inhibit neoplasia and pharmaceutical compositions containing such compounds | |
| KR20080106404A (ko) | Ｐｄｚ 상호작용의 소형 분자 억제제 | |
| JP5931876B2 (ja) | 多発性嚢胞腎を処置するためのレセプタータイプキナーゼの調節因子の使用 | |
| AU697120C (en) | Method and compositions for inhibition of adaptor protein/tyrosine kinase interactions | |
| TW200410937A (en) | 3-imino-2-indolones for the treatment of depression and/or anxiety | |
| JP2004536127A (ja) | キナーゼ阻害剤及びその使用 | |
| HK1147417A (en) | Kinase protein binding inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20201222 |